Auricular nerve field stimulation device and methods for using the same

ABSTRACT

A method for treating pain or discomfort in a patient is disclosed. The method comprises stimulating a cranial nerve with an electrical signal. The pain or discomfort may be a withdrawal symptom. The cranial nerve may be in an auricular area of the patient. The cranial nerve may be cranial nerve V, cranial nerve VII, cranial nerve IX, cranial nerve X, or branches of greater and lesser occipital nerves thereof and their associated neurovascular bundles. The withdrawal symptom may result from cessation of an opioid. The method may further comprise administering a secondary drug treats one or more of the withdrawal symptoms and addiction. The secondary drug may be administered about one day to about one week after initiating the stimulating step.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 16/534,159, filed on Aug. 7, 2019, which is a continuationapplication of U.S. application Ser. No. 15/488,416, filed on Apr. 14,2017, now U.S. Pat. No. 10,413,719, issued Sep. 17, 2019, which claimsthe benefit of priority under 35 U.S.C. § 119(e) to U.S. ProvisionalPatent Application Ser. No. 62/323,369, filed Apr. 15, 2016, and U.S.Provisional Application Ser. No. 62/324,598, filed Apr. 19, 2016, eachof which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention described herein pertains to devices and methods fortreatment of disease by nerve stimulation. More particularly, thepresent disclosure is related to treating disease including but notlimited to pain and drug withdrawal by implanting a device in theperi-auricular area to stimulate cranial nerves.

BACKGROUND

Drug Withdrawal

Opioid addiction is a serious public health issue that negativelyimpacts many communities around the world. There are millions of peoplewho misuse opioids worldwide. In 2013, it was estimated that in theUnited States, approximately 1.9 million people suffered from substanceuse disorders related to prescription opioid pain relievers andapproximately 517,000 were addicted to heroin. Currently, mostindividuals with an opioid use disorder are not able to get treatment.

Abrupt discontinuation of heroin or an opioid receptor agonist for thepurpose of transitioning to an opioid antagonist, such as naltrexone,requires an “induction phase” including medical supervision to controlsymptoms. Areas of the brain and brainstem which are normallyresponsible for homeostasis are typically suppressed by opiates alteringboth function and the ability to adapt. After removal of the opiatesthese areas may respond by becoming hyperactive before returning tohomeostasis. Certain treatment options, such as antagonists, cannot beprescribed until patients have successfully completed medicallysupervised withdrawal due to the risk of inducing a precipitatedwithdrawal. For example, naltrexone completely blocks opiate receptorsbut cannot be used until the patient is opiate free for several days ora precipitated withdrawal may occur. Extended release forms ofnaltrexone, which may be effective for the prevention of relapse intoopioid dependence, may require seven days or more of a detox process toavoid precipitated withdrawal. Another common complication is the returnto opiate use after withdrawal leading to overdose deaths.

Pharmacotherapy has been the main method for the induction phase oftreatment of opioid withdrawal. There are challenges tomedication-assisted treatment for acute opiate withdrawal and opiateaddiction. Some medications for treatment of opiate detox are themselvesaddicting. For example, methadone and buprenorphine are partial opiatereceptor agonists that stimulate opiate receptors. Non-narcoticmedications, such as clonidine, anti-spasmodics, and sleeping aids, haveunpredictable efficacy. Naloxone, which is an antidote to heroin oropiate overdose, can be life-saving, but has a short half-life and doesnot provide an efficacious treatment for long-term sobriety.

Patients are more likely to leave treatment early when withdrawalsymptoms are not appropriately managed. Pain associated with withdrawalis often a major reason for opting out of treatment. Symptoms ofwithdrawal may include, but are not limited to, abdominal cramping,diarrhea, cold and hot sweats, dilated pupils, cutis anserine, nausea,vomiting, dehydration, electrolyte disturbances, heart arrhythmias, andaspiration of stomach contents into the lungs leading to lunginfections.

Thus, there is a need in the art for methods of treating opioidwithdrawal during the period between cessation at least up untiladministration of a drug such as a pharmaceutical opiate receptorblocking drug. Moreover, there is a need to find an effective,non-pharmacological approach to treat opioid withdrawal, which couldremove some of the barriers associated with pharmacotherapy.

Pain Relief

Additionally, analgesia has traditionally been achieved throughmedication. For example, acute and chronic pain conditions have beentreated with opioid or opioid derivative medications. These medicationshowever, are associated with adverse side effects that limit their use.Accordingly there is also a need for new treatment methods to providerelief of pain and discomfort.

Functional Abdominal Pain Disorders

Functional abdominal pain disorders (FAPDs) are a group of functionalgastrointestinal disorders with pain as the driving symptom. Examples ofFAPDs include irritable bowel syndrome (IBS), functional dyspepsia,functional abdominal pain-not otherwise specified (FAP-NOS) andabdominal migraine. Patients with irritable bowel syndrome (IBS) sufferfrom chronic abdominal pain despite having no structural or anatomicallesions. Most pharmacological agents used to treat IBS are no better orhave minimal gain over placebo. Their complex nature and unclearpathophysiology may make the management of FAPDs challenging.Accordingly there is also a need for new treatment methods to providerelief of FAPDs.

Throughout this disclosure, various publications, patents and patentapplications are referenced. The disclosures of these publications,patents and applications in their entireties are hereby incorporated byreference into this disclosure.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing patients' COWS scores over time before andduring treatment with the Bridge;

FIG. 2 shows a response of an amygdala neuron before and after auricularstimulation; and

FIG. 3 shows a response of a lumbar spinal neuron before and afterauricular stimulation.

SUMMARY OF THE INVENTION

In some embodiments, the present disclosure provides a method fortreating pain and/or discomfort in a patient in need of such treatment.The method comprises stimulating a cranial nerve with an electricsignal. For example, the may comprise administering to the patient astimulator device that provides the electric signal. The device may beany device configured to electrically stimulate nerves near thepatient's auricular area. The stimulating step can be administeredprophylactically, or can be administered after the onset of thesymptoms.

The methods described herein may be used for various therapeuticapplications. In some embodiments the methods are used to treat pain byproviding analgesia. In further embodiments the methods are used totreat drug addition. A stimulator device may mitigate withdrawalsymptoms upon application to a patient. For example, the withdrawalsymptoms may be associated with opioids withdrawal. In still furtherembodiments, the methods are used to treat the symptoms associated witha functional abdominal pain disorder.

In accordance with some embodiments, the method comprises a first stepof stimulating a patient's cranial nerve soon after cessation of drug oralcohol use. The stimulation step may occur for several days. Themethods described herein may further comprise administering one or moresecondary drugs during or after the stimulating step.

Several embodiments of the invention are described by the followingenumerated clauses:

1. A method for treating pain or discomfort in a patient comprisingstimulating a cranial nerve with an electrical signal.

2. The method of clause 1, wherein the pain or discomfort is awithdrawal symptom.

3. The method of clause 1, wherein the pain or discomfort is afunctional abdominal pain disorder.

4. The method of clause 3, wherein the functional abdominal paindisorder is irritable bowel syndrome.

5. The method of any of the preceding clauses, wherein the cranial nerveis in an auricular area of the patient.

6. The method of any of the preceding clauses, wherein the cranial nerveis in a peri-auricular area of the patient.

7. The method of any of the preceding clauses, wherein stimulating thecranial nerve comprises contacting the auricular area of the patientwith the electrical signal.

8. The method of any of the preceding clauses, wherein stimulating thecranial nerve comprises contacting the peri-auricular area of thepatient with the electrical signal.

9. The method of any of the preceding clauses, wherein the cranial nerveis selected from the group consisting of cranial nerve V, cranial nerveVII, cranial nerve IX, cranial nerve X, and branches of greater andlesser occipital nerves thereof and their associated neurovascularbundles.10. The method any of the preceding clauses, wherein the cranial nerveis selected from the group consisting of cranial nerve V, cranial nerveVII, cranial nerve IX, and cranial nerve X.11. The method of any of clauses 2 and 5 to 10, wherein the withdrawalsymptom results from cessation of an addictive drug or alcohol.12. The method of any of clauses 2 and 5 to 11, wherein the withdrawalsymptom results from cessation of an addictive drug.13. The method of clause 11 or 12, wherein the patient abstains fromusing the addictive drug during the stimulating step.

14. The method of any of clauses 11 to 13, wherein the addictive drug isselected from the group consisting of an opioid, cocaine or a base orsalt thereof, nicotine, an amphetamine or substituted amphetamine, abarbiturate, alcohol, a benzodiazepine, or buprenorphine.

15. The method of any of clauses 11 to 14, wherein the addictive drug isan opioid.

16. The method of clause 15, wherein the opioid is selected from thegroup consisting of morphine, codeine, heroin, hydrocodone, oxycodone,buprenorphine, methadone, nicomorphine, dipropanoylmorphine,desomorphine, acetylpropionylmorphine, dibenzoylmorphine,diacetyldihydromorphine, paramorphine, fentanyl, pethidine, levorphanol,tramadol, tapentadol, dextropropoxyphene, hydromorphone, oxymorphone,ethylmorphine, buprenorphine, and salts thereof.17. The method of clause 15 or 16, wherein the opioid is selected fromthe group consisting of heroin, hydrocodone, oxycodone, morphine,fentanyl, and codeine.18. The method of any of clauses 2 and 5 to 17, wherein the withdrawalsymptoms comprise conditions selected from the group consisting ofabdominal cramping, diarrhea, cold sweats, hot sweats, dilated pupils,cutis anserine, nausea, vomiting, increased heart rate, restlessness,somatic pain, runny nose, gastrointestinal symptoms, tremors, yawning,anxiety, irritability, fear, and combinations thereof.19. The method of any of the preceding clauses, further comprisingadministering a secondary drug to the patient.20. The method of clause 19, wherein the secondary drug treats one ormore of the withdrawal symptoms and addiction.21. The method of clause 19 or 20, wherein the secondary drug isadministered about one day to about two weeks after initiating thestimulating step.22. The method of any of clauses 19 to 21, wherein the secondary drug isadministered about one day to about one week after initiating thestimulating step.23. The method of any of clauses 19 to 22, wherein the secondary drug isan opioid receptor antagonist.24. The method of any of clauses 19 to 23, wherein the secondary drug isselected from the group consisting of naloxone, naltrexone, andnalmefene.25. The method of any of clauses 19 to 24, wherein the secondary drug isnaltrexone.26. The method of any of the preceding clauses, further comprising usingtransillumination to locate auricular neurovascular bundles of thepatient.27. The method of any of the preceding clauses, wherein the stimulatingstep occurs for about ten minutes to about one week.28. The method of any of the preceding clauses, wherein the patientexperiences a reduction in the pain or discomfort within one day.29. The method of any of clauses 2 and 5 to 28, wherein the patientexperiences a reduction in the withdrawal symptoms within one day.30. The method of any of clauses 2 and 5 to 29, wherein the patientexperiences a reduction in the withdrawal symptoms within one hour.31. The method of any of the preceding clauses, wherein the stimulatingstep comprises administering electrical stimulation pulses to theauricular area of the patient.32. The method of clause 31, wherein the electrical simulation pulseshave a voltage output of about 1V to about 5V.33. The method of clause 31 or 32, wherein the electrical simulationpulses have a repetition frequency of about 0.5 Hz to about 100 Hz.34. The method of any of clauses 31 to 33, wherein the electricalsimulation pulses have a repetition frequency of about 1 Hz to about 10Hz.35. The method of any of clauses 31 to 34, wherein the electricalsimulation pulses have a duty cycle of about 10% to about 90%.36. The method of any of clauses 31 to 35, wherein the electricalsimulation pulses have a duty cycle of about 40% to about 60%.37. The method of any of clauses 31 to 36, wherein the stimulationpulses are generated at a constant current amplitude.38. The method of any of the preceding clauses, wherein the stimulatingstep comprises attaching a stimulator device to the auricular area ofthe patient.39. The method of any of the preceding clauses, wherein the stimulatingstep comprises attaching a stimulator device to the peri-auricular areaof the patient.40. The method of clause 38 or 39, wherein the stimulator device isattached percutaneously or transcutaneously.41. The method of any of clauses 38 to 40, wherein the stimulator devicecomprises

(i) a generator for generating electrical stimulation pulses withdefined stimulation parameters, (ii) a voltage supply for supplying thegenerator with electrical energy and (iii) a control device forgenerating stimulation pulses from the generator having a definedcurrent voltage or current amplitude, a defined duration, a definedrepetition frequency and a defined duty cycle and

at least one therapy electrode connected to the stimulator for providingstimulation pulses to the auricular area.

42. The method of any of clauses 38 to 41, wherein the device isimplanted within 2 mm the cranial nerve.

43. The method of any of the preceding clauses, wherein the stimulatingstep alters response characteristics of amygdala neurons.

44. The method of any of the preceding clauses, wherein the stimulatingstep alters response characteristics of lumbar spinal neurons.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with Applicants' invention described herein, theembodiments of the numbered clauses provided in the summary above, orany combination thereof, are contemplated for combination with any ofthe embodiments described in the Detailed Description section of thispatent application.

Definitions

In describing and claiming the invention, the following terminology willbe used in accordance with the definitions set forth below.

The term “about” as used herein means greater or lesser than the valueor range of values stated by 10 percent, but is not intended todesignate any value or range of values to only this broader definition.Each value or range of values preceded by the term “about” is alsointended to encompass the embodiment of the stated absolute value orrange of values.

As used herein, the term “pharmaceutically acceptable carrier” includesany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions such as an oil/water orwater/oil emulsion, and various types of wetting agents. The term alsoencompasses any of the agents approved by a regulatory agency of the USFederal government or listed in the US Pharmacopeia for use in animals,including humans.

As used herein the term “pharmaceutically acceptable salt” refers tosalts of compounds that retain the biological activity of the parentcompound.

As used herein a “effective” conditions refers to nontoxic butsufficient conditions to provide the desired effect. For example, onedesired effect would be preventing the onset of withdrawal symptoms, orreducing the severity, frequency, or duration, of such symptoms.Conditions constituting “effective” will vary from subject to subject,depending on the age and general condition of the individual, mode ofadministration, and the like.

In accordance with the invention, “clinical benefit” means a response ofa patient to treatment with a stimulating method described herein wherethe response includes overall reduction or pain and/or discomfort,potentially among other clinical benefits.

In accordance with the invention, the term “administering” as usedherein includes all means of introducing the stimulating methods anddevices described herein to the patient.

Electrical Nerve Field Stimulation

Percutaneous Electrical Neuro-modulating Field Stimulation (PENFS) is anon-narcotic treatment that may be used for conditions such as acutepost-surgical and chronic pain conditions, thereby reducing thelong-term side effects, dependency, and opiate abuse associated withmore traditional pharmacological protocols. PENFS also may be used tomitigate opioid withdrawals. PENFS may also be used for headachecontrol, and other types of pain, including pre and post surgical painand acute and chronic pain. Although this disclosure refers toPercutaneous Electrical Neuro-modulating Field Stimulation, methods ofimplementation beyond percutaneous implementation, such astranscutaneous implementation are within the scope of PENFS.

In some embodiments, devices capable of accomplishing PENFS arepercutaneously or transcutaneously implanted into the peri-auriculararea of a patient, targeting cranial nerves V, VII, IX and X; andbranches of the greater and lesser occipital nerves and their associatedneurovascular bundles. The external ear contains branches of thesenerves, which project to the nucleus tractus solitarius (NTS) andcommunicate with other brain structures involved in autonomic controland pain such as the amygdala. The dorsal and ventral aspects of theauricle are heavily vascularized from branches of the superficialtemporal artery (STA) and the posterior auricular artery (PAA). CranialNerves V, VII, IX, X; as well as branches of the greater and lesseroccipital nerves are also present in a predicable anatomical fashion.Thus, in some embodiments, the method comprises a clinician to targetingspecific cranial neurovascular bundles.

The methods described herein may comprise stimulated sources ofextrinsic perivascular innervation, such as those that carry sensory,sympathetic, and parasympathetic nerves. A neurovascular unit includesthe functional unit of the endothelial cells, perivascular nerves, andastrocytes. These nerves have different origins and neurotransmittersthat can be extrinsic or intrinsic. The external auricle is includes allthree embryological tissues that can have influences on the autonomicnervous system. In particular, the trigeminal nerve, vagus nerve, andcervical plexus innervate different areas of the ear. The methodsdescribed herein may comprise stimulating one or more of the trigeminalnerve, the vagus nerve, and the cervical plexus.

The theauriculotemporal branch of the trigeminal nerve (CN V) suppliesthe anterior upper part of the helix consisting mostly of mesodermaltissue. This nerve runs with the superficial temporal artery thatsupplies the ear. The vagus nerve (CN X) innervates the auricular conchawhich consists mostly of endodermal tissue. The auricular branch of thevagus nerve passes into the jugular fossa and enters the superior vagalganglion where their nerve cell bodies are located. Finally, the lesseroccipital nerve (C3) innervates the posterior part of the helix and thegreat auricular nerve (C2, C3) innervates the auricular lobule both ofwhich are mostly ectodermal in embryological origin.

The extended amygdala has been shown to play a role in not only fearconditioning and pain processing, but also in processing the negativeemotional state of withdrawal. The methods and devices described hereinmay be utilized to treat these symptoms. For example, in someembodiments, the devices and methods described herein may show areduction in the baseline firing of neurons in the central nucleus ofthe amygdala and a decrease in response to somatic stimulation. In someembodiments, the methods and devices described herein result inneuromodulation of limbic structures that could help alleviate symptomsof withdrawal and offer a noninvasive, drug free alternative.

The apparatuses and methods disclosed herein may reduce sympatheticactivity and increase parasympathetic activity by electrical stimulationof the associated cranial nerve bundles via percutaneous implantation ofneedle arrays into the dermis of the peri-auricular region. Withoutintending to be bound by theory, it is believed that the methods anddevices describes herein activate the nucleus tractus solitarious (NTS),the hypothalamus, the amygdala, and the rostral ventromedial medulla(RVM), affecting both sympathetic and parasympathetic feedback loopsinto the gray matter of the dorsal horn of the spinal column. As such,the methods and devices described herein may result in disruption ofascending nociceptive stimuli and blocking of descending signalsreleasing endogenous endorphins and other cytokines often associatedwith hyperactivity of the previously mentioned entities during opiatewithdrawal.

In some embodiments, the methods disclosed herein may alleviate orreduce one or more withdrawal symptoms. Without intending to be bound bytheory, the noradrenergic system may be involved in the expression ofthe somatic symptoms during opiate withdrawal indicating changes inbrain noradrenaline and metabolite levels during opiate dependence. Thesympathetic nervous system becomes hyperactive and the hypothalamus, thepituitary gland, and the locus coeruleus begin working at above normallevels increasing activity of the peripheral sympathetic nervous system(SNS) during opiate withdrawal, as measured by increases in plasmalevels of norepinephrine. Compensatory dysregulation of the sympatheticnervous system co-joined with the hypothalamic-pituitary-adrenal axis,the periaqueductal gray (PAG) area, the amygdala, the ventral tegmentalarea, nucleus accumbens, and spinal cord lead to an excess of bodilyfunctions normally inhibited by opiates which often include miosis.Mouths may overly dry, mydriasis may occur, dry skin may begin toperspire, dry noses may begin to run, and insensitivity to temperaturemay develop quickly into hot/cold flashes and chills and precipitationof the physical motor components of opiate withdrawal.

These fluctuations also contribute to excess cortisol release, emotionalvulnerability, an inability to fall asleep, anxiety, agitation, panicattacks, increased heart rate, increased blood pressure, muscle tension,tremors, restlessness (akathisia), involuntary movements of the limbs,nausea, vomiting, and stomach discomfort. Other commonly observedsymptoms including diarrhea and lacrimation may depend on peripheralopiate receptors. By applying the methods of the present disclosure suchsymptoms may be alleviated or reduced.

In the peripheral nervous system (PNS), beta-endorphins produceanalgesia by binding to opioid receptors at pre- and post-synaptic nerveterminals, primarily exerting their effect via presynaptic binding. Whenbound, a cascade of interactions results in inhibition of the release oftachykinins, particularly substance P, a key protein involved in thetransmission of pain contributing to allodynia and hyperalgesia commonlyexperienced during opiate withdrawal. As stated above, the methods ofthe present may alleviate or reduce one or more of these symptoms.

Additionally, persistent irritation of the microglia distorts thefeedback patterns of the neuromatrix with subsequent endocrine, immune,and autonomic nervous system changes; and impairs descending medullaryinhibition. Without intending to be bound by theory, it is believed thatthe methods and devices described herein reduce this irritation and theassociated microglial inflammation.

In one embodiment, the methods and devices described herein can be usedfor both human clinical medicine and veterinary applications. Thus, a“patient” can be administered a method herein, and can be human or, inthe case of veterinary applications, can be a laboratory, agricultural,domestic, or wild animal. In one aspect, the patient can be a human, alaboratory animal such as a rodent (e.g., mice, rats, hamsters, etc.), arabbit, a monkey, a chimpanzee, domestic animals such as dogs, cats, andrabbits, agricultural animals such as cows, horses, pigs, sheep, goats,and wild animals in captivity such as bears, pandas, lions, tigers,leopards, elephants, zebras, giraffes, gorillas, dolphins, and whales.

In reference to opioid withdrawal, the Clinical Opiate Withdrawal Scale(COWS) scoring system may be used to evaluate alleviation of a patient'ssymptoms. In some embodiments, withdrawal symptoms are reduced withinabout 5 minutes, about 15 minutes, about 20 minutes, about 30 minutes,about 60 minutes, about 2 hours, about 3 hours, or about 6 hours. Forexample, a patient's COWS scores may be reduced by greater than about25%, greater than about 50%, or greater than about 60% within 20 minutesafter initiation of nerval stimulation. In some embodiments, a patient'sCOWS scores may be reduced by greater than about 50%, greater than about75%, or greater than about 80% within 60 minutes after initiation ofnerval stimulation.

Advantageously, the methods and devices disclosed herein constitute aneffective, non-pharmacological approach that may 1) entail minimalclinician training, 2) be readily available to physicians and advancedcare providers, 3) have minimal to no side-effects, and 4) remove thefear of inducing a precipitated withdrawal would be critical inimproving and expanding treatment for opioid addiction. In someembodiments, the methods and devices described herein can be used byphysician extenders without limitations on the number of subjectstreated. In general, the methods and devices described herein offerrapid and effective improvement could lead to improved compliance andbetter treatment outcomes.

Electrical Nerve Field Stimulation Devices

The nerve may be stimulated by a stimulator device including a generatorfor generating electrical stimulation pulses with defined stimulationparameters. The stimulator may comprise at least one needle electrodearray for insertion into the skin surface of an area to be stimulated.Also, the stimulator device may comprise a power supply for supplyingthe generator with electrical energy.

One example of device included in the present disclosure are thosedescribed in U.S. Patent Pub. No. 2015/0112405, incorporated byreference herein in its entirety.

Another example of group of percutaneously implanted devices of thepresent disclosure is the Neuro-Stem System (NSS), Innovative HealthSolutions, INC, Versailles, Indiana. The NSS collectively refers todevices including the Bridge devices, Innovative Health Solutions, INC,Versailles, Indiana, the Electro Accupuncture Device (EAD), InnovativeHealth Solutions, INC, Versailles, Indiana, and the Military FieldStimulator (MFS), Innovative Health Solutions, INC, Versailles, Indiana.The devices may be safe, fast-acting, and effective in pain relief andreduction in pain medication consumption.

More particularly, the NSS may be a group of neuro-stimulation medicaldevices each comprising a battery operated solid state generatorexternally affixed to the skin behind a patient's ear, four wireconnecting leads, and four attached electrode/needle arrays eachincluding four 1.5 mm needles designed to be percutaneously implantedinto the dermis of the patient's external ear.

In one embodiment, the auricular peripheral nerve stimulators of thepresent disclosure are a battery-operated, single-use devices that havea preprogrammed frequency, pulse, and duration for the stimulation ofselected cranial and/or peripheral nerves and corresponding neuralvascular bundles of auricular and periauricular areas. In oneembodiment, the device power supply connects via three or moreelectrical conduit wires, sheathed in electrically insulating material,to one or more therapy electrode arrays comprised of multiple needleseach and one reference electrode.

In another embodiment, the device comprises two or more needle arrayscomprised of multiple needles each. In another embodiment, the devicecomprises three or more needle arrays comprised of multiple needleseach. In another embodiment, the device comprises four or more needlearrays comprised of multiple needles each. In another embodiment, theneedle arrays are comprised of two or more needles each. In anotherembodiment, the needle arrays are comprised of three or more needleseach. In another embodiment, the needle arrays are comprised of four ormore needles each. In another embodiment, the needle arrays arecomprised of five or more needles each. In another embodiment, theneedle arrays are comprised of six or more needles each.

The stimulation devices of the present disclosure may include agenerator for generating stimulation pulses with defined stimulationparameters, such a defined voltage or a defined current, a definedduration, a defined repetition frequency and a defined duty cycle.

The electrical stimulation device electrical stimulation pulses may havea repetition frequency of about 0.5 to about 100 Hz, about 0.5 to about50 Hz, about 0.5 to about 25 Hz, about 0.5 to about 10 Hz, about 1 toabout 100 Hz, about 1 to about 50 Hz, about 1 to about 25 Hz, or about 1to about 10 Hz. Also, the electrical stimulation device electricalstimulation pulses may have a duty cycle of about 10 to about 90%, about10 to about 70%, about 20 to about 90%, about 20 to about 70%, about 30to about 90%, about 30 to about 70%, or about 40 to 60%. In someembodiments, the stimulation pulses are generated at a constant currentamplitude.

In some embodiments, the stimulation conditions may be adjusted based ona patient's muscle activity, parameters corresponding to breathing, orparameters corresponding to cerebral activity, such as electricalactivity of neural cells including brain cells, or electrical activityrecorded from the ear or any other suitable point on the body of a humanbeing. Other sensors may be applied as well, like a sensor to measurebody temperature, a sensor to measure pressure, and a sound sensor, likea microphone.

In some embodiments, each therapy electrode has two or more needleelectrodes, which in an exemplary embodiment is four (4) in number. Inone embodiment, the number of therapy electrodes is selected from thegroup consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more. In anotherembodiment, the number of needle electrodes per therapy electrode isselected from the group consisting of 2, 3, 4, 5, 6, 7, 8, 9, 10, ormore. In one embodiment, the number of needle electrodes per therapyelectrode is 2-10. In one embodiment, the number of needle electrodesper therapy electrode is 3-9. In one embodiment, the number of needleelectrodes per therapy electrode is 4-8.

Each reference electrode includes at least at least one needleelectrode. The therapy electrodes and reference electrode are insertedinto the skin surface in the area to be stimulated. The referenceelectrode provides a ground connection for electronic circuit locatedwithin the stimulator.

The devices of the present disclosure provide an apparatus forstimulating auricular points on the human ear is provided using lowvoltage pulses that are generated and delivered by portions of theapparatus, particularly by percutaneously implanted needle electrodesinto the cranial and/or peripheral nerves and corresponding neuralvascular bundles of the auricular and periauricular areas.

In order to attach the devices described herein to a patient's skinsurface, a fastening element, such as an adhesive element, may beprovided. Besides the adhesive element, other fastening methods, e.g.via magnets, elastic bands or the like can be used.

In another embodiment, the devices described herein are single usedevices that are physician applied for ambulatory, continuous, homebased therapy. These devices may be percutaneously implanted into thecranial and/or peripheral nerves and corresponding neural vascularbundles of the auricular and periauricular areas as ascertained by thedisclosed method of evaluating and implanting of the electrode/needlearray. This includes transillumination of the auricular andperiauricular tissues and surrounding neurovascular anatomy. Theauricular peripheral nerve stimulator system allows for continuous,intermittent neural stimulation for about 1 day, about 2 days, about 3days, about for days, or about 5 days.

In another embodiment, the devices are ambulatory, physician applied,minimally invasive applications of electrical neural stimulationimplanted directed into the neurovascular bundles of the external earverified by transillumination co-joined with skin impedance measurement.In another embodiment, a generator located behind the ear, produceselectrical stimulation impulses, which are transferred via anelectrode/needle array to branches of cranial and/or occipital nervesand sympathetic fibers of the arterial branches.

In another embodiment, electrode/needle array implantation into the skinof the ear allows for direct access to branches of cranial nerves V,VII, IX, and X as well as branches of the occipital nerves. Directaccess to the arterial branches of the head and neck are accessible andreduction of sympathetic stimulation results in an increase of vascularflow rate, reduction of vascular resistance and increase of perfusion.The arterial branches of the superficial temporal artery and theposterior auricular artery form a rich interconnecting complex networkthe terminal branches of which anastomose throughout the ear.

In another embodiment, the auricular peripheral nerve stimulator altersproduction and utilization of serotonin via vagal stimulation, andmeningovascular dilation secondary to decreased sympathetic (orincreased parasympathetic) tone.

In some embodiments, the devices described herein are provided indisposable convenience kits comprising one or more of a generator,sterile wire leads with arrays attached, transilluminator, tweezers,surgical marking pen, several adhesives, bandages, disinfectant, and IFU(instructions for use).

Methods of Electrical Nerve Field Stimulation

The methods described herein may comprise using a stimulator device. Thedevice may be physician applied for ambulatory, continuous, home basedtherapy. In one embodiment, a stimulator is percutaneously implantedinto the cranial and/or peripheral nerves and corresponding neuralvascular bundles of the auricular and periauricular areas as ascertainedby the method of evaluating and implanting of the electrode/needle arrayprovided in the present invention. This includes transillumination ofthe auricular and periauricular tissues and surrounding neurovascularanatomy. The auricular peripheral nerve stimulator system allows forcontinuous, intermittent neural stimulation.

First, the chosen external ear may be cleaned with an astringent toremove any surface oils or debris. Furthermore, the subject's externalear and the generator location may be disinfected by alcohol pads.

Next, the patient's ear is transilluminated to identify neurovascularbundles that are to be avoided during needle implantation. Moreparticularly, methods described herein may include transillumination ofthe auricular and periauricular tissues and surrounding neurovascularanatomy depending upon the symptoms or other conditions of a particularpatient. It should be appreciated that one skilled in the art canidentify auricular points and/or their correlation with differenthealth. Once such points are identified by a health care professional,the device of this invention is employed to deliver a pulsed voltage tosuch points.

Visualization may be accomplished due to the thickness of the tissue ofthe external ear being thin enough that a focused light(transilluminator) can pass through the tissue (transillumination).Also, there is a difference in density between the auricular tissues andthe auricular neurovascular bundles allowing the bundles to bevisualized and outlined. In other embodiments, both measurement of therate of arterial blood flow and the vessel anatomy can be visualized andisolated using ultra sonic imaging and other techniques used to directlyvisualize neurovascular or vascular tissues.

The verification of the cranial nerves, peripheral nerves, arterialbranches, and neurovascular bundles may be ascertained by anatomy andvisualization. There are anatomical areas (zones), which havepredictable and reproducible concentrations of the cranial nerves,peripheral nerves, arterial branches, and neurovascular bundles but noset “points” to learn and follow. The combination of the understandingof anatomy, visualization, and proper percutaneous implantation of theneedle/electrode array may determine proper transfer of the electricityinto the neurovascular bundles.

Also, as discussed above, the dorsal and ventral aspects of the auricleare heavily vascularized from branches of the superficial temporalartery (STA) and the posterior auricular artery (PAA). Cranial Nerves V,VII, IX, X; as well as branches of the greater and lesser occipitalnerves are also present in a predicable anatomical fashion. In someembodiments, this helps the clinician to target specific cranialneurovascular bundles.

In one particular embodiment, a lighted, optic tip of atransillumination device is placed directly against the skin on theventral or dorsal aspect of the ear at 90 degrees so the concentratedlight passes through the tissue. The light can be a direct, focusedlight or an array of lights of any color spectrum. Since the lightpasses through the tissue and the auricular tissue has a differentdensity than the neurovascular bundles, this may in essence outline thearterial branches and the neurovascular vascular bundles so they can beseen.

Random percutaneous implantation of the arrays into a heavilyvascularized area could result in a high incidence of bleeding. Thetechnique of transillumination avoids random placement and may helpreduce the incidence of insertion directly into the peripheral arterialbranches, greatly reducing the potential of bleeding. The use of FDAapproved bio-compatible materials, sterilization of the arrays andproper skin disinfecting technique, as outlined in the IFU (instructionsfor use) reduces the incidence of dermatitis, and practically eliminatesthe chance of infection.

The electrode/needle complex(s) may be implanted to stimulate the nervesincluding but not limited to the arterial branches, the cranial nerves,peripheral nerves, and the neurovascular bundles. The generator may beattached with adhesive to the skin behind the ear just over the mastoidprocess. Needles are inserted into the dorsal and ventral aspects of theear. The needles may be placed within about 1 to about 1.5 mm of thevisible arterial branches to create a field effect. In some embodiments,the electrode/needle array connected to the lead wires arepercutaneously implanted into the proper anatomical location being sureto penetrate the skin so implantation is percutaneous within about 1 mmor within about 2 mm of the chosen neurovascular bundles. The devicesmay be implanted using a percutaneous or transcutaneous approach.

There is a natural tissue resistance to electricity. The implantedneedle cannot be directly into an arterial branch. Percutaneousimplantation of one or more needle/electrode complex(s) or an arraybeyond the capability of the tissue to transfer the electricity willcause tissue damage and pain with little or no energy transfer to theneurovascular bundles, arterial branches, peripheral or cranial nerves.Percutaneous implantation of a needle or needle/array directly into amain arterial branch will cause pain and bleeding.

In one particular embodiment, the needle/electrode complex(s) isimplanted percutaneously within 2 mm of the neurovascular bundles (asvisualized) but not directly into an arterial branch by placing theneedle into the skin at 90 degrees from either the dorsal or ventralaspect of the ear depending upon which of the cranial nerves, occipitalnerves, neurovascular bundles, or arterial branches are to be targeted.The needle should not be inserted directly into a main arterial branch.The needle must pass through the outer dermis to be classified aspercutaneous. Placing any type of stimulation to the outer skin withoutcomplete skin penetration is considered transcutaneous.

The actual location and determination of needle placement (calledpoints) may be similar to those of the tradition and theory ofacupuncture. However, the present invention provides methods not basedupon acupuncture technique or “points” but rather peripheral nerve fieldstimulation, anatomical location of cranial nerves, peripheral nerves,arterial branches and/or neurovascular bundles, and energy transferbased upon accepted laws of energy transfer in human tissue. Therefore,in some embodiments, the method does not require precise placement ofneedles in specific “acupoints.” Peripheral nerve field stimulationconsiders neuro-anatomy, blood vessel anatomy, proximity of theelectrodes to the actual nerves being stimulated, and verification ofelectrode proximity.

The methods described herein vary from auricular acupuncture in severalways. For example, the verification of the bundles may ascertained byphysical anatomy and visualization; there are anatomical areas, whichhave concentrations of the cranial nerves and arterial branches but noset “points” to learn and follow; location of placement of theelectrode/needle complex must be individualized and is not “pre set;”and the methods comprise neurovascular stimulation and targetedstimulation of the cranial nerves or peripheral nerves, not acupuncturepoints (chi, hot/cold, or reflex points).

Verification of correct placement may be determined by patients notingthe pulsing of the electricity, and/or enlarging of the associatedarteries by unaided visual inspection. In one embodiment, the methodfurther comprises following up with transillumination as describedherein to help verify arterial reaction. In another embodiment, themethod further comprises measurement of an increase in blood flow, asmeasured or determined by any method or device.

In some embodiments, upon percutaneous implantation and activation of agenerator, a fractal geometric electronic field is produced which isdesigned to stimulate the targeted neurovascular bundles.

The methods may comprise delivering about 0.5V to about 10V, about 1V toabout 7V, about 1V to about 5V, about 2 to about 4V or about 3.2V. Thevoltage may be delivered with alternating frequencies of stimulation.

The methods described herein may be applied for about 10 minutes, about15 minutes, about 30 minutes, about 1 hour, about 3 hours, about 6hours, about 12 hours, about 1 day, about 2 days, about 3 days, about 4days, about 5 days, up to about 10 minutes, up to about 15 minutes, upto about 30 minutes, up to 1 about hour, up to 3 about hours, up to 6about hours, up to about 12 hours, up to about 1 day, up to about 2days, up to about 3 days, up to about 4 days, up to about 5 days, or upto about 7 days. In some embodiments, stimulation is provided for atotal of about 120 hours, allowing for physician applied ambulatorytreatment of acute pain secondary to opiate withdrawal.

The method may comprise careful monitoring of the patient's vital signsand the availability of immediate supportive care. In some embodiments,a patient is assessed by measuring heart rate, sweating, restlessness,pupil size, somatic pain, runny nose, GI upset, tremors, yawning,anxiety or irritability, gooseflesh skin, or a combination thereof. Insome embodiments, due to the stimulation of the peripheral branches ofthe Vagus nerve, possible vaso-vagal response may be taken intoconsideration. Patient's pre-existing health conditions such asseizures, bleeding disorders, on-demand electrical implants,medications, and autonomic nervous system status may be taken intoconsideration.

Depending upon the type of pain or discomfort as described herein, awide range of permissible conditions for treatment are contemplatedherein. The treatment sessions may be single or divided, and mayadministered according to a wide variety of protocols, including q.d.,b.i.d., t.i.d., or even every other day, biweekly (b.i.w.), once a week,once a month, once a quarter, and the like. Further, a staggeredregimen, for example, one to five days per week can be used as analternative to daily treatment, and for the purpose of the methodsdescribed herein, such intermittent or staggered daily regimen isconsidered to be equivalent to every day treatment and is contemplated.In various embodiments of the invention, the methods and devicesdescribed herein may be administered more than once and intermittently.By “intermittent administration” is intended administration of effectiveconditions, followed by a time period of discontinuance, which is thenfollowed by another administration of the effective conditions.Additional treatment sessions may be administered to the patient toprevent the recurrence of withdrawal symptoms.

Any effective regimen for administering the devices and methodsdescribed herein can be used. Effective conditions, as herein defined,may be dependent upon many factors, including but not limited to, thetype of disease or condition and its severity, i.e., the extend of thepatient's pain or discomfort, the patient's general health, size, age,and the nature of the treatment, i.e. short-term or chronic treatment.

As further described herein, the methods of the present disclosure leadto low reported incidences of bleeding, dermatitis, infection, andsyncope support these positions. Nevertheless, in some embodiments themethods described herein further comprise monitoring of the patient'svital signs and/or immediate availability of supportive care.

Secondary Drugs

In accordance with one embodiment of the present disclosure, the methodsdescribed herein further comprise co-administering one or more secondarydrugs. The term “co-administered” as used herein means that thesecondary drug may be administered together with the devices and methodsof the present disclosure as part of a single treatment step or asseparate, multiple steps. For example, the secondary drug can beadministered before, after, or in conjunction with the methods anddevices of the present disclosure to enhance or supplement theireffectiveness in treating pain or discomfort. In accordance with oneembodiment the patient is treated with the methods and devices describedherein, immediately followed by the secondary drug. Advantageously, whenthe methods and devices described herein are administered in conjunctionwith other agents used for treating pain or discomfort, the amount ofthe active agents needed for efficacy may be reduced relative to whenone agent is used alone.

Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of the bridge agent.The co-administration of a bridge agent and a second therapeutic agent,to a patient does not preclude the separate administration of that sametherapeutic agent, any other second therapeutic agent or any compound ofthis invention to the patient at another time during a course oftreatment.

In some embodiments the device is administered during the time periodwhen a patient is susceptible to precipitated withdrawal. For example,the device may be used for about 1 day, about 2 days, about 3 days,about 4 days, or 5 days before administering the secondary drug.

In some embodiments, the methods described herein may further compriseadministering a secondary drug for the treatment of withdrawal symptoms.The secondary drug may be an opioid receptor antagonist. For example,secondary drug may be naloxone, naltrexone, or nalmefene.

The aversive and anxiety-like state during withdrawal is thought toinvolve stress-related systems such as noradrenergic pathways. In someembodiments, the methods described herein further comprise administeringone or more drugs that inhibit noradrenergic release such as clonidine.

In some aspects of these embodiments, a parenteral dosage form selectedfrom the group consisting of intradermal, subcutaneous, intramuscular,intraperitoneal, intravenous, and intrathecal may be employed toadminister the secondary drug.

In some embodiments the secondary drug is provided as a salt. Suitableacid addition salts are formed from acids which form non-toxic salts.Illustrative examples include the acetate, aspartate, benzoate,besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate,citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate,glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride,hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate,maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate,nicotinate, nitrate, orotate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate,succinate, tartrate, tosylate and trifluoroacetate salts.

Suitable base salts of the secondary drug described herein are formedfrom bases which form non-toxic salts. Illustrative examples include thearginine, benzathine, calcium, choline, diethylamine, diolamine,glycine, lysine, magnesium, meglumine, olamine, potassium, sodium,tromethamine and zinc salts. Hemisalts of acids and bases may also beformed, for example, hemisulphate and hemicalcium salts.

In one embodiment, a patient is administered a composition comprisingthe secondary drug in a standard pharmaceutically acceptable carrierusing any of the standard routes of administration known those skilledin the art. The carriers can be excipients. The choice of carrier willto a large extent depend on factors such as the particular mode ofadministration, the effect of the carrier on solubility and stability,and the nature of the dosage form. Pharmaceutical compositions suitablefor the delivery of second compound described herein and methods fortheir preparation will be readily apparent to those skilled in the art.Such compositions and methods for their preparation may be found, forexample, in Remington: The Science & Practice of Pharmacy, 21th Edition(Lippincott Williams & Wilkins, 2005), incorporated herein by reference.

In one illustrative aspect, a pharmaceutically acceptable carrierincludes any and all solvents, dispersion media, coatings, antibacterialand antifungal agents, isotonic and absorption delaying agents, and thelike, and combinations thereof, that are physiologically compatible. Insome embodiments, the carrier is suitable for parenteral administration.Pharmaceutically acceptable carriers include sterile aqueous solutionsor dispersions and sterile powders for the extemporaneous preparation ofsterile injectable solutions or dispersions. Supplementary activecompounds can also be incorporated into compositions of the invention.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thesecondary drug is administered transdermally (e.g., using a transdermalpatch or iontophoretic techniques). Other formulations may convenientlybe presented in unit dosage form, e.g., tablets, sustained releasecapsules, and in liposomes, and may be prepared by any methods wellknown in the art of pharmacy.

In certain embodiments, the secondary drug is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In one aspect, a secondary drug as described herein may be administereddirectly into the blood stream, into muscle, or into an internal organ.Suitable routes for such parenteral administration include intravenous,intraarterial, intraperitoneal, intrathecal, epidural,intracerebroventricular, intraurethral, intrasternal, intracranial,intratumoral, intramuscular and subcutaneous delivery. Suitable meansfor parenteral administration include needle (including microneedle)injectors, needle-free injectors and infusion techniques.

In various embodiments, formulations may be for immediate and/ormodified release. In one illustrative aspect, active agents of thesecondary drug compound may be administered in a time releaseformulation, for example in a composition which includes a slow releasepolymer. The second compound can be prepared with carriers that willprotect the second compound Biodegradable, biocompatible polymers can beused, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid,collagen, polyorthoesters, polylactic acid and polylactic, polyglycoliccopolymers (PGLA). Methods for the preparation of such formulations aregenerally known to those skilled in the art. In another embodiment, thesecondary drug described herein may be continuously administered, whereappropriate.

In one embodiment a kit is provided for administering the devices andsecondary drugs described herein to a patient. The kit comprises adevice of the present disclosure, optionally one or more secondarydrugs, and optionally means for separately retaining the compositions,such as a container, divided bottle, or divided foil packet. Dependingon the route of administration, the kit may include an inhaler if saidsecond composition is an inhalable composition; a syringe and needle ifsaid second composition is an injectable composition; a syringe, spoon,pump, or a vessel with or without volume markings if said composition isan oral liquid composition; or any other measuring or delivery deviceappropriate to the dosage formulation of the composition present in thekit. In one embodiment the kit is provided with a device foradministering the second composition to a patient, e.g. syringe needle,pen device, jet injector or other needle-free injector. In oneembodiment the device is a syringe. In some embodiments, the kitincludes instructions for use of the bridge and optionally one or moresecondary drugs.

Opioid Withdrawal

Some embodiments of the present disclosure relate to treating a patientsuffering from withdrawal symptoms. Patients suffering from suchsymptoms are treated using the methods and devices described herein, ina manner and for a time sufficient to reduce the severity, frequency orduration of their symptoms.

In some embodiments, the methods described herein further compriseadministering an opioid receptor antagonist to a patient in needthereof. In illustrative embodiments, the opioid receptor antagonist maybe naloxone, naltrexone, or nalmefene, or an extended releaseformulation thereof. In further embodiments, the opioid receptorantagonist may be naltrexone or an extended release formulation thereof,such as Vivatrol®. The antagonist may be administered to a patient afterinitiating neuronal stimulation or after completing neuronalstimulation. For example, a patient may be treated using the methods anddevices described herein leading up to the time that the patient may beadministered an opioid receptor antagonist without risk of precipitatedwithdrawal.

Advantageously, the methods described herein offer a non-narcotic optionto opiate detox and also have the potential for shortening thetransition from opioid use to an opioid receptor antagonist, such asVivitrol®, while mitigating withdrawal symptoms. Such a protocol mayhave particular utility regarding incarcerated individuals minimizingemergency department treatment and reducing costs secondary towithdrawal symptoms.

Without intending to be bound by theory, the methods described hereinmay include disrupting ascending nociceptive stimuli and blocking ofdescending signals releasing endogenous endorphins and other cytokinesoften associated with hyperactivity of the previously mentioned entitiesduring opiate withdrawal. The physical components commonly associatedwith opioid withdrawal are a result of the complex interaction ofbiological feedback loops influenced by the autonomic nervous system.Peri-auricular percutaneous electrical nerve field stimulation thedevices described herein is an efficacious way to help reduce symptomsoften associated with opioid withdrawal by stimulating areas of thebrain via cranial nerves concentrated in the peri-auricular dermisgreatly reducing symptoms commonly associated with opioid withdrawal.

In some embodiments, the withdrawal symptom treated by the methods anddevices described herein include one or more of abdominal cramping,diarrhea, cold sweats, hot sweats, dilated pupils, cutis anserine,nausea, vomiting, increased heart rate, restlessness, somatic pain,runny nose, gastrointestinal symptoms, tremors, yawning, anxiety,irritability, fear.

Analgesia and Hemodynamics

In some embodiments, stimulating cranial nerves by peri-auricular PENFSmay alter intracranial hemodynamics. More particularly, the methodsdisclosed herein provide a nonpharmaceutical approach to alteration ofintracranial hemodynamics to achieve analgesia.

In some embodiments, the methods disclosed herein stimulate the cranialnerves anatomically located in the peri-auricular area directlyaffecting the extrinsic perivascular innervation, as well as themicro-vascular bed, of the intracranial arteries to decrease flowresistance and increase cerebral perfusion.

Auto-regulation of cerebral blood flow refers to the ability to maintaina relatively constant blood flow despite changes in perfusion pressure.Auto-regulation is particularly well developed in the brain. Chronicpain, inflammation, neuropsychiatric disorders, and stress may alter theautonomic nervous system and bias ANS/CNS auto-regulation throughmultiple pathways.

Neuromodulation using the methods and devices of the present disclosurealters hemodynamics of cerebral circulation. These devices and methodsproduce significant changes in cerebral hemodynamics as a result ofcranial nerve stimulation.

Neuromodulation utilizing the methods and devices of the presentdisclosure may be administered as a therapeutic approach for painconditions. Such treatment may be aimed at reducing the long-term sideeffects, dependency, and opiate abuse associated with more traditionalpharmacological protocols. Stimulation of cranial and cervical nervesdescribed herein may have an effect on the neuromatrix, altering theneuro-modulating feedback loops; resulting in pain reduction.Stimulating these cranial nerves, and their posited effects upon theneuromatrix also may predict altered autonomic modulation ofintracranial hemodynamics.

Without intending to be bound by theory, the neuromatrix theory predictspain perception and response to be moderated by a series of entangledfeedback loops, consistent with the maintenance of homeostasis. Itfurther predicts pain-modulating factors outside of the somatic sensorypathways. Several cranial and cervical nerves participate in both thesomatic and exo-somatic pathways of the neuromatrix, and thus painmodulation. Among these are CN's V, VII, X, and occipital nerve, theterminal branches of which are represented in the external humanauricle.

In some embodiments, hemodynamics may be measured using transcranialDoppler (TCD). As used herein, TCD refers to a noninvasive ultrasoundevaluation of the cerebral arteries in real-time. It involves using alow frequency, e.g. 2 MHz or less, transducer on specific bone windowsto allow for dynamic monitoring of cerebral blood flow velocity andvascular resistance.

Combined with waveform morphology, indices derived from flow velocityreadings including the Gosling's pulsatility index (PI) and thePourcelot resistivity index (RI) identify increased cerebral vascularresistance and hyper dynamic flow states, which may be used tocharacterize certain clinical conditions. The TCD ultrasound uses pulsedwave Doppler to image at various depths, and the received echoesgenerate electrical pulses in the ultrasound transducer that areprocessed to produce spectral waveforms with peak systolic velocity andend diastolic velocity values.

In some embodiments, the NSS neuromodulation device stimulates theextrinsic perivascular innervation and the micro-vascular bed todecrease flow resistance and increase cerebral perfusion afterpercutaneous implantation and activation in the peri-auricular region.Peripheral vascular constriction is a result of sympathetic stimulation.Vagal stimulation can reduce sympathetic drive.

In some embodiments, the methods and devices described herein produce aneuro-modulating signal ranging from about 1 to about 10 kQ in intervalsof about 100 ms, a bipolar impulse width of about 1 ms with a duty cycleof about 2 hr duty/2 hr rest for a total of about 120 hours.

Amygdala

In some embodiments, neurostimulation with the methods and devicesdescribed herein decreases the baseline firing of amygdala neurons andattenuates the response to somatic stimulation. The amygdala, inparticular, is a brain region which is involved in pain processing, andactivation of this area has also been associated with the emotionalcomponent of pain and fear conditioning and the negative emotional stateof withdrawal to opioids and drug craving.

Attenuation may occur within about 10 minutes, within about 15 minutes,within about 30 minutes, or within about 1 hour. Without intending to bebound by theory, this attenuation may modulate pain responses in bothhumans and animals as well as improve in the negative emotional stateassociated with drug withdrawal.

Lumbar Spinal Neurons

In some embodiments, neurostimulation with the methods and devicesdescribed herein may also alter the response characteristics of lumbarspinal cord neurons. More particularly, neurostimulation with themethods and devices described herein may decrease the spontaneous firingand response to somatic stimulation of lumbar spinal neurons. In furtherembodiments, auricular stimulation as described herein influences thedescending modulatory effect on spinal neurons.

Abdominal Pain

In some embodiments, the methods and devices described herein may beused as a non-pharmacological treatment option for patients with chronicabdominal pain, such as functional abdominal pain disorders includingbut not limited to irritable bowel syndrome (IBS). In some embodiments,the methods described herein result in about 10%, about 20%, about 30%,or about 40% improvement in abdominal pain. Abdominal pain may bemeasured based on patient reported outcomes (PROs). In some embodiments,auricular neurostimulation as described herein may significantly preventthe development of post-inflammatory visceral and somatichypersensitivity, such as that associated with TNBS colitis.

Hyperalgesia occurs with IBS and refers to an exaggerated pain responseto a normally noxious stimulus. Visceral and somatic hyperalgesis canoccur in humans and animals following inflammation in the colon. In someembodiments, a patient develops chronic IBS following a gastrointestinalinfection.

The methods and devices described herein include the following examples.The examples further illustrate additional features of the variousembodiments of the invention described herein. However, it is to beunderstood that the examples are illustrative and are not to beconstrued as limiting other embodiments of the invention describedherein. In addition, it is appreciated that other variations of theexamples are included in the various embodiments of the inventiondescribed herein.

Example 1

This study aimed to determine the effects of the Bridge, InnovativeHealth Solutions, INC, Versailles, Indiana, on withdrawal scores duringthe induction phase of opioid withdrawal therapy and the percentage ofsubjects who successfully transitioned to medication assisted therapy(MAT).

Adult patients (≥18 years old) who met DSM-IV criteria for opioiddependence and voluntarily presented to outpatient drug treatmentclinics between June 2015 and July 2016 were included in thisretrospective study. Inclusion criteria included a minimum age of 18years old and a history of dependence on heroin or other opioids such asprescription narcotics, methadone, and buprenorphine/naloxone. A totalof 73 subjects were included. In this cohort, the mean age was 32.9years old and 65% were male. The mean length of drug use was 70 monthsand 90.5% of the subjects had been using opioids for at least 2 years.68% of patients had used heroin, 23% had used prescription narcotics,33% had used buprenorphine/naloxone, and 7% had used methadone. Patientswere excluded if they reported a history of dependence on alcohol,pregnancy, or inability to consent to the treatment. A history ofbenzodiazepines or marijuana use was not a contraindication to Bridgeplacement. Participating clinics located in St. Louis, MO, Liberty, IN,Florence, KY, Anchorage, AK, Rising Sun, IN, Richmond, IN, Dayton, OH,and Indianapolis, IN provided data from patients treated with theBridge. The participating treatment centers provided individualizedevaluation, stabilization, and treatment with a team of physicians,nurses, counselors, and case managers. Variations exist among the eightoutpatient clinics with an approximate daily census ranging from 4 to 25patients.

Medical records were reviewed for every opioid-dependent individual whowas voluntarily treated with the Bridge. Data obtained from all subjectssuch as demographics and history that included age, gender, approximatelength of addiction, and substances used were obtained from chartreview. Urine analysis to screen for concomitant use of other substanceswas performed prior to start of treatment in all patients.

Initial Clinical Opioid Withdrawal Scale (COWS) scores were recorded atbaseline and at 20, 30, and 60 minutes in all patients. These scoreswere extracted from the chart along with scores recorded 5 days afterBridge placement, when available. The scores ranged from 0 to 48 and arerated as mild (5-12), moderate (13-24), moderately severe (25-36), orsevere (>36).

Each patient's ear was cleaned with alcohol wipes and transilluminatedto identify neurovascular bundles to be avoided during needleimplantation. The generator was attached with adhesive to the skinbehind the ear just over the mastoid process. There were four leads thatcame off of the generator, each with sterile 2 mm titanium needles thatwere inserted into the dorsal and ventral aspects of the ear. The arraywas place in four general areas within 1-1.5 mm of the visible arterialbranches to create a field effect. The Bridge delivered 3.2V withalternating frequencies of stimulation and had a battery life of 5 days.

Patients were observed after Bridge placement, and the majority was senthome after symptoms of withdrawal were relieved, usually after the firsthour. The use of any rescue medications during the first hour ofneurostimulation with the Bridge, including antipsychotics, narcotics,or benzodiazepines, was also recorded. Patients were instructed tofollow up within 1 to 5 days, depending on the clinic, and to leave thedevice on for the entire 5-day period to prevent the recurrence ofsymptoms. Any adverse outcome associated with the device was recordedincluding localized pain, infections, or neurological complaints notrelated to withdrawal. Informed consent was not obtained due to theretrospective study design.

The main outcome measured was reduction in withdrawal scores as measuredby the COW scale. Although the primary outcome of this study was toassess improvement in symptoms during withdrawal from opioids,successful transition to MAT was also investigated in a subset ofpatients. Those subjects returning to clinic on day 5 post-Bridgeplacement and receiving their first dose of maintenance medication withthe opioid receptor antagonist, naltrexone, were considered to besuccessfully transitioned.

Statistical analysis was performed with SPSS version 19. Basicdescriptive statistics were used for participant demographics.Nonparametric analysis with repeated measures ANOVA was used to evaluateeffectiveness in reducing withdrawal scores across all time periodsmeasured. Missing COWS scores were encountered at 20 min (11/73) and at60 min (2/73). Imputing of missing data was not performed, and analysiswas made only with available data since the missing values wereconsidered missing at random. Data were presented as mean (±standarddeviation), and p<0.05 was considered statistically significant.

Immediately prior to Bridge placement, the majority of patients in thisstudy, 53/73 (72.6%), fell into the moderate withdrawal range, while16/73 (21.9%) were in the moderately severe range and 4/73 (5.4%) werein the mild range. In the entire cohort, the mean (standard deviation)COWS score prior to Bridge placement was 20.1 (±6.1). The Bridgedecreased scores to a mean of 7.5 (±5.9) by 20 minutes (62.7% reduction,p<0.001), 4.0 (±4.4) by 30 minutes (80% reduction, p<0.001), and 3.1(±3.4) after 60 minutes (84.6% reduction, p<0.001), as shown in FIG. 1 .Overall, 73/73 (100%) subject had a reduction in COW scores by 60minutes with a minimum decrease in at least 36.4%. At 60 minutes 57/73(78.0%) had withdrawal scores of ≤3. No rescue medications were used inany subject during the first 60 minutes after device placement. Duringthe entire 5-day period, no antipsychotic, narcotic or benzodiazepinemedications were given. Thirty eight percent (28/73) of patientsreceived an antiemetic.

A subset of patients also had withdrawal scores recorded 5 days afterBRIDGE placement and prior to transitioning to MAT (n=33). For thesepatients, the average withdrawal score prior to receiving the first doseof naltrexone was 0.6 (97.1% reduction). In the entire cohort of 73patients, 64 (88.8%) successfully transitioned to MAT after Bridgeplacement. No adverse events were recorded in any subject during theentire time of neurostimulation with the Bridge.

Example 2

In this Example, all patients involved treated were in the acute phaseof heroin or opiate withdrawal as verified by the Clinical OpiateWithdrawal Scale (COWS), a self-report assessment tool for measurementof opiate withdrawal symptoms.

Data was collected on 8 cases. Six had addiction to prescription opiatepain medications and two had heroin addiction. Four were men and fourwere women and all were Caucasian, with a mean age of 33.2 years(SD=7.1). All patients were in moderate to moderately-severe withdrawalbased on COWS scale. The Bridge device was implanted and patients wereobserved in the clinic for at least one hour before being sent home.Medications were not given in the clinic in order to observe acuteBridge device effects. However patients were given the traditionalnon-narcotic rescue medications to take at home per request.

Pre-post COWS data were available for 7/8 patients (one missingpost-test). The pre-test mean COWS of 21.9 (SD=5.5) was significantlyreduced at post-test to 6.1 (SD=5.2), t(6)=5.5, p=0.0015. However, thepost-test for one of these patients was obtained the following day. Ofthe 6 patients for whom COWS data were obtained in clinic, after a meaninterval of 32.5 minutes (SD=14.7), mean COWS scores were 23.1 (SD=5.1)at pre-test and 5.9 (SD=5.6) at post-test, t(5)=5.7, p=0.0024. Time toVivitrol treatment data were available for 7/8 patients (one pending):4/7 patients (57%) transitioned to Vivitrol in less than 7 days(mean=3.1 days, SD=0.8). The remaining 3 patients were non-compliantwith follow-up, resulting in times to Vivitrol of 12, 28, and 140 days.Clinical questioning also indicated that, in addition to significantreduction in COWS scores, patients experienced an improvement of overallmood, decreased sense of distress, and reduction of non-pain symptomssuch as goose pimples, rhinorrhea, and restlessness (consistent withstimulation of the para-sympathetic tone). There were no adverse effectsassociated with the device.

The Bridge device was associated with a significant reduction in opiatewithdrawal symptoms. Without intending to be bound by theory, sinceheroin or opiate withdrawal is a combination of opiate receptordysfunction and a hyperactive sympathetic nervous system, the Bridgedevice is believed to stimulate para-sympathetic activity via auricularneuro-vascular bundles containing cranial Nerve's V, XII, IX and X, andlocalized cervical nerves reducing hyper-excitability motor statesassociated with adrenergic tone as well as stimulating endogenousendorphins to relieve pain symptoms associated with opiate withdrawal.The average time of the reduction of the COWS scores of 32.5 minutes inthis Example may be the result of the nucleus tractus solitarius (NTS)relaying signals to the amygdala and the rostral ventral medulla (RVM)and associated spinal wind-up.

Example 3

This Example investigated the intracranial hemodynamic effect ofperi-auricular PENFS. For this study the Electro Accupuncture Device(EAD), Innovative Health Solutions, INC, Versailles, IN, was used. Thetreatment protocol produced significant changes in cerebral hemodynamicsas a result of direct cranial nerve stimulation as detected byTranscranial Doppler ultrasonography.

The EAD was powered by 3 1V batteries. After activation the deviceproduced a neuro-modulating signal ranging from 1-10 kQ in intervals of100 ms, a bipolar impulse width of 1 ms with a duty cycle of 2 hr duty/2hr rest for a total of 120 hours.

A single 10-minute percutaneous neuromodulating stimulation wasperformed on a cohort of 12 healthy adult patients during a 3-week span.The cohort, ages 19-64, were randomly recruited. The subjects wereinterviewed individually. Past medical and surgical histories werecollected and screened for potentially disqualifying morbidities. Allsubject's questions were answered to the subject's satisfaction.Informed consents were signed. Patients were appointed individually atthe test site. Upon arrival, the subjects were informed of the nature ofthe study. Prewritten instructions were read to assure uniformunderstanding of the instructions. After instructions were read, vitalsigns were taken and recorded.

Statistics for the variables that were measured prior to EADimplantation and TCD ultrasound measurements are presented in Table 1.The data were used to access any clinical indications for potentiallydisqualifying morbidities.

TABLE 1 Collected data before TCD ultrasound measurements (N = 12) AgeSystolic Diastolic Pulse Temperature O₂ Air Weight Height BMI Mean 34.6122.5 74.6 76.6 97.9 98.4 161.0 66.8 25.8 Median 24.5 124.0 76.0 78.097.8 99.0 154.5 66.0 25.0 Minimum 19.0 104.0 62.0 56.0 97.2 93.0 125.863.0 20.0 Maximum 64.0 148.0 88.0 92.0 98.5 100.0 220.0 71.0 33.0 Std.Dev 16.9 15.0 8.0 9.8 0.4 2.1 30.2 2.4 3.9

Each subject was placed on an exam table in the supine position. Foreach subject, the chosen ear was disinfected with a 70% isopropylalcohol pad and left undisturbed for 10 minutes.

After 10 minutes, a baseline TCD assessment of hemodynamics of themiddle cerebral, anterior cerebral, posterior cerebral, basilar, invertebral arteries was performed. Each TCD ultrasound assessmentinvolved measuring the blood flow (mean, peak systolic, and enddiastolic) velocities and the downstream cerebral resistance usingGosling's pulsatility index (PI) and Pourcelots resistivity index (RI).The mean velocity, peak systolic velocity, end diastolic velocity (Edv),PI and RI are designated as “Pre-mean”, “Pre-Peak”, “Pre-Edv”, “Pre-PI”and “Pre-RI” for the anterior cerebral artery (ACA), the middle cerebralartery (MCA), and the posterior cerebral artery (PCA).

Next, a NSS sham Device, which had no batteries and percutaneous needlesremoved, was then placed according to protocol. Before application ofthe device, the serial number and bar code of the device was recorded.Each patient was placed in the supine position and left undisturbed for10 minutes. Thereafter, the flow in the transcranial arterial brancheswas measured using a TCD ultrasound and recorded. The mean velocity,peak systolic, end diastolic velocity, PI and RI values are respectivelypresented as “Sham-mean”, “Sham-Peak”, “Sham-Edv”, “Sham-PI” and“Sham-RI” for the ACA, MCA, and PCA. The sham device was then removedand disposed.

Next, the subject was left undisturbed for 10 minutes before an activeNSS device was placed in a similar way as the shame device. Thereafter,the activated NSS device was implanted according to protocol. Following10 minutes of NSS device activation, a TCD ultrasound assessment ofhemodynamics of the arterial branches performed as previously indicated.The mean velocity, peak systolic velocity, end diastolic velocity, PIand RI data are respectively presented as “Tx-mean”, “Tx-Peak”,“Tx-Edv”, “Tx-PI” and “Tx-RI” for the ACA, MCA, and PCA.

The mean baseline flow in the ACA was found to be 37.3±7.3 cm/s(mean±standard deviation). Upon activation, the mean flow was 46.5±8.1cm/s. The mean PI and RI before activation were both ≤1.0±0.1, butdecreased to 0.8±0.1 and 0.6±0.1 upon activation, respectively.

The baseline mean flow in the PCA was found to 35.6±4.9 cm/s. Afterimplantation of the active NSS device, the mean flow rate rose to36.0±3.9 cm/s. The baseline PI and RI were 1.0±0.2 and 0.6±0.1,respectively. When an active NSS device was implanted, both the mean PIand RI remained almost unchanged.

The mean MCA baseline flow was found to be 53.1±9.3 cm/s, and 59.4±11.8cm/s after the active NSS device was implanted. Even after activation,the PI and RI remain almost constant at 0.9±0.2 and 0.6±0.1.

Based on a 2-tailed independent sample tests (p=0.05), the ACA, PCA, andMCA data was tested for correlation. The following variables werestatistically significantly and positively correlated (p<0.05):Pre-Edv-ACA and Pre-Mean-ACA (p=0.01, r=0.838); TX-PI-PCA and TX-RI-PCA(r=0.98). The TX-PI-ACA significantly statically positively correlatedto all MCA (PI, RI, Mean, Peak, EDV). The Peak-ACA and Mean-ACA werenegatively correlated to both PI and RI. The Pre-Mean-ACA, Sham-Mean ACAand the TX-Mean values are weakly negatively correlated to PI-MCA andRI-MCA.

The ACA, PCA and MCA data was tested for any significant differences invariables due to differences in treatments using paired samples t-test(5% Significance level). Paired means that were statisticallysignificantly different are presented in Table 2.

TABLE 2 Paired samples test indicating statistically significantdifferences (p < 0.05) between the paired means. Upper and lower limitswere calculated at 95% confidence level. Mean Std. Dev. Lower Upper tp-value Pre_ACA-Tx_ACA −8.675 10.2426 −15.183 −2.1672 −2.934 0.014pre_Peak_ACA-Sham_Peak_ACA −10.8317 11.7884 −18.322 −3.3417 −3.183 0.009Pre_Edv_ACA-Sham_Edv_ACA −6.863 5.3084 −10.236 −3.4902 −4.479 0.001Pre_PI_ACA-Sham_PI_ACA 0.0931 0.0885 0.0368 0.1494 3.642 0.004Pre_PI_ACA-Tx_PI_ACA 0.1031 0.1568 0.0034 0.2027 2.276 0.044Pre_RI_ACA-Sham_RI_ACA 0.0243 0.0317 0.0041 0.0444 2.651 0.023pre_Peak_PCA-Sham_Peak_PCA 6.9167 7.8313 1.9409 11.8924 3.060 0.011pre_Peak_MCA-Tx_Peak_MCA −7.7106 10.3095 −14.261 −1.1603 −2.591 0.025Pre_Edv_MCA-Tx_Edv_MCA −3.9962 5.4508 −7.4595 −0.5330 −2.540 0.027

EAD application changed the mean hemodynamic flow in the cerebralarteries, increasing by 1-19%, while the PI and RI values decreased by2-11% from the baseline. Therefore, this Example demonstrates anincrease in cerebral perfusion by decreasing resistance (decrease PI andRI) to outflow, and a significant increase in mean flow velocity wasobserved, which was consistent with an increase in cerebral perfusionvia cerebral micro-circulatory recruitment. These results support thatperi-auricular implantation of the EAD stimulates the cranial nervesanatomically located in the peri-auricular area affecting the extrinsicperivascular innervation, as well as the micro-vascular bed, of theintracranial arteries to decrease flow resistance and increase cerebralperfusion, and trigger autoregulatory mechanisms within the cranium.

Example 4

A group of 5 rats underwent extracellular single-unit recordings fromneurons in the central nucleus of the amygdala (CeA). Animals wereanesthetized with Urethane (induction, 1.5 g/kg, i.p.; maintenance, 0.05mg/kg intravenously bolus to maintain plane of anesthesia).Physiological parameters including respiratory rate, heart rate and corebody temperature (kept at 37° C.) were continuously monitored. Eachanimal was mounted in a stereotaxic frame and a small unilateralcraniotomy was made to allow for the insertion of the recordingelectrode. Single-unit recordings from neurons were made withglass-insulated carbon filament electrodes (4-6 MΩ). The followingstereotaxic coordinates were used: 2.2 to 3.1 caudal to bregma, 3.8 to4.2 lateral to midline, depth 6.5 to 8.0. The action potentials wereamplified through a low-noise AC differential amplifier (model 3000; AMSystems) and continuously monitored and displayed on an oscilloscope. Adual window discriminator (modelDDIS-1; BAK Electronics) was used todiscriminate the action potentials and to convert the signal to arectangular TTL pulse. The frequency of TTL pulses was counted on-lineby using the Spike 2/CED 1401 data acquisition system (CambridgeElectronic Design). Action potentials and blood pressure were recordedon-line. After the experiments, data were analyzed using the Wave-Markanalysis method of the Spike 4 software (Cambridge Electronic Design) todistinguish individual action potentials.

In each animal, background and evoked activity of only one neuron wasrecorded from the right amygdala. An individual neuron was identified byits background activity and responses to brief search stimuli, whichincluded compression of deep tissue (left paw) with a consistent forceusing Von Frey filaments. In each experiment, one amygdala neuron thatresponded to paw compression was selected and recorded. The backgroundactivity in the absence of any intentional stimulation was recorded for5 min. Following the baseline recording, a 30 s compression of the pawwas applied twice with the same Von Frey filament (190 mN) 5 min apart.After recording two compressions, the Bridge device was connected to theear on the ipsilateral side and left undisturbed for 15 minutes. Thebaseline firing of the neuron and response to compression of the paw wasagain recorded.

Statistical analysis was performed using SigmaStat (V2.03, SPSS Inc,Chicago, IL). Baseline firing and response of the neurons to paw pinchwas measured as action potential counts over 30 sec compression of thepaw and were analyzed using one-way repeated.

Extracellular recordings from amygdala neurons were made in 5 rats. Atotal of 5 neurons that responded to noxious stimuli (compression) ofthe hind paw were recorded. All neurons were classified as excitatorywith cutaneous receptive fields mainly in the trunk and plantar surfaceof the paw. A typical response of an amygdala neuron before and afterauricular stimulation is shown in FIG. 2 , where the top trace showsresponse as a frequency histogram with 1 s bin width, the middle traceis neuron action potential, and the bottom trace is pay pinch duraction.

Prior to auricular stimulation, the mean spontaneous firing of theneurons was 1.15±0.36 imp/sec with an excitatory response to 3.05±0.46after paw pinch (190 mN). There was a 52% decrease in the spontaneousfiring of the neurons after just 15 minutes of auricular stimulationwith the Bridge (0.56±0.21 imp/sec). Similarly, the response tocompression of the paw was decreased by approximately 66% afterauricular stimulation (1.04±0.29 imp/sec) (p<0.05).

Example 5

The incidence of clinically observed bleeding, localized dermatitis andinfections at the implantation sites of the electrode/needle arrays,dermatitis at the site of the generator, and patient syncope wasquantified. A total of 1207 Neuro-Stem System (NSS), Innovative HealthSolutions, INC, Versailles, IN, devices, each producing up to 16percutaneous punctures, for a total of 19312 punctures were monitoredfor adverse effects, based on retrospective chart audits conducted at 6clinical facilities over a one-year period.

All patients from the 6 participating centers, who qualified withinaccepted clinical guidelines, for placement of the NSS were included inthis study. Both male and female patients, aged 16 to 70 years, wereincluded in the study. Licensed clinicians were asked to retrospectivelyreview their charting for the outlined adverse patient observations.

The six centers, which were from a wide geographic and interdisciplinarybackground performed a retrospective chart audit for the preceding 12months to ascertain the incidence of specified adverse reactions toplacement of a total of 1207 NSS devices. Each device had four electrodearrays consisting of 4 needles which were percutaneously implanted intothe dorsal or ventral aspect of the external ear for a total of 16percutaneous punctures per application. The result is a total cohort of19,312 percutaneous punctures. Data from four different categories wascollected:

-   -   Bleeding at any puncture site    -   Dermatitis at any puncture site    -   Dermatitis at the generator attachment site    -   Syncope at time of implantation

The data on discomfort upon insertion of the electrodes from sixdifferent treatment centers is presented in Table 3. Out of a total19312 punctures, 10 episodes of bleeding and 11 episodes of localizeddermatitis were observed at the electrode, respectively. No incidencesof syncope (fainting) or infection were observed. There were no reportedincidences of syncope in this cohort. This report of findings supports aclassification of minimal risk.

TABLE 3 Number of NSS device placements and the reported number ofincidences of bleeding, dermatitis, severe pain, and syncope from fivedifferent treatment centers. Center A Center B Center C Center D CenterE Center F NSS devices 144 141 67 614 151 90 Bleeding 2 2 0 5 1 1Dermatitis 2 2 0 6 1 0 Severe pain 0 0 0 2 0 0 Syncope 0 0 0 0 0 0

Example 5

Rats were anesthetized with an initial dose of urethane (induction, 1.5g/kg, i.p) and maintained by bolus dosing through the right femoral vein(0.05 mg/kg). The left carotid artery was also cannulated to monitorblood pressure. Following tracheal intubations, the rats were paralyzedwith an initial dose of gallamine triethiodide (10 mg·kg⁻¹ i.v.,Flaxedil) and mechanically ventilated with room air (˜60 strokes·min⁻¹).Subsequent doses of gallamine triethiodide (5 mg·kg⁻¹·h⁻¹) were given asneeded to maintain paralysis. The body temperature was kept withinphysiological range (36-37° C.) with an overhead lamp. The rats wereplaced in a stereotaxic head holder and the thoraco-lumbar (T13-L2)spinal cord was exposed by laminectomy. After removal of the duramembrane, a 1-2 cm saline-soaked gelatin sponge (Gelfoam, PharmaciaUpjohn Company, MI USA) was employed to cover the exposed spinal cordsegment. The skin was reflected laterally to make a pool for agarsolution that was allowed to cool to 38° C. prior to pouring. The agarwas allowed to harden and the dorsal surface of the spinal cord wasexposed by removing a cubical slice of agar with a scalpel blade. Theexposed surface of the spinal cord was covered with warm mineral oil(37° C.).

Extracellular single-unit recordings were performed on two rats from thelumbar (L1-L2) spinal segments using glass-insulated, carbon filamentelectrodes. The placement of the electrode was 0.1-0.5 mm lateral fromthe spinal midline and 0.6-1.8 mm ventral from the dorsal surface. Theaction potentials were amplified through a low-noise AC differentialamplifier (model 3000; A-M Systems) and continuously monitored anddisplayed on an oscilloscope. A dual window discriminator (model DDIS-1;BAK Electronics) was used to discriminate the action potentials and toconvert it to rectangular TTL pulse. The frequency of TTL pulses wascounted online by using the Spike2/CED 1401 data acquisition system(Cambridge Electronic Design). Action potentials and blood pressure wererecorded. Post experiments, data were analyzed using the Wave-Markanalysis method of the Spike 4 software (Cambridge Electronic Design) todistinguish individual action potentials.

The spontaneous neuronal activity was recorded for each neuron followedby recording of responses to noxious pinch of the paw using Von Freyfilament (190 N) for 10 seconds. After obtaining the baseline response,the Bridge device was attached to the contralateral ear. After 15minutes of stimulation, the baseline firing and response to paw pinchwas again recorded.

One neuron from each animal (n=2) that responded to compression of thehind paw were recorded. All neurons were classified as excitatory andhad cutaneous receptive fields mainly in the ipsilateral rump area. Anexample of one spinal neuron recorded before and after stimulation withthe Bridge device is shown in FIGS. 3A and 3B, respectively. Eachfrequency histogram in the FIGS. 3A and 3B has a 1 s bin width.

Following stimulation with the Bridge, there was a decrease in thespontaneous baseline firing of the neurons (4.6±0.21 imp/sec) comparedto pre-stimulation (9.5±0.43 imp/sec). Similarly, firing of the neuronsin response to pinching of the paw was much lower after auricularstimulation (7.7±0.24 imp/sec) compared to the pre-stimulation response(15.8±1.43 imp/sec).

Example 6

This Example evaluated the efficacy, safety, and tolerability of a 3week trial of Neuro-Stem System (NSS), Innovative Health Solutions, INC,Versailles, IN vs. placebo in children with FAPDs.

This study was a double-blind, randomized, placebo-controlled study thatincluded children ages 11-18 years who satisfied criteria for a FAPDbased on the Rome III version of the Questionnaire on PediatricGastrointestinal Symptoms (QPGS) and weekly symptoms as assessed by theprovider for any of the four FAPDs including irritable bowel syndrome(IBS), functional dyspepsia, functional abdominal pain-not otherwisespecified (FAP-NOS), and abdominal migraine. Subjects were required tohave an average daily pain rate ≥3 out of 10 (on a 0 to 10-pointnumerical rating scale for worst abdominal pain the week prior tostarting the trial). The primary end point was determined using the PainFrequency-Severity-Duration (PFSD) scores. The PFSD is a validated paintool for children designed to incorporate multiple aspects of the painexperience with 3 major weekly scores: usual pain (0-10), worst pain(0-10) and number of days in pain (0-7). Groups were compared forimprovement in worst pain over the 3 week treatment and the PFSDcomposite score for all 3 measures. The composite score was derived bymultiplying the number of days of pain, the level of usual pain, and thelevel of worst pain and then dividing the product by 10. The highestpossible score was 70. The key secondary end point percentage ofpatients who achieved a clinical response at week 3, defined as apatient who reported a decrease of ≥30% in weekly worst abdominal painfrom baseline. This primary outcome was based on the FDA recommendationfor IBS in adults and the ROME foundation pediatric subcommittee onclinical trials in children. Also, the proportion of patients who hadglobal improvement of at least +2 in the weekly symptom response scale(SRS) was used as a secondary outcome. Several studies have demonstratedthat when using 7-point scale response options in disease-specificmeasures, a change in score of 0.5 represents the minimally importantdifference. A change of 1.0 is considered a moderate change in qualityof life, and a change in score greater than 1.5 is likely to represent alarge change.

For analysis of the PFDS scores, 30% improvement in pain, and symptomsresponse scale, the Fisher's exact test was used to compare categoricalvariables and the Mann-Whitney test was used to compare continuousvariables. Time, treatment group, and time×treatment group werepredictors. All data are presented as mean±S.E.M. Comparison betweengroups was based on intention-to-treat (ITT) principle. A p-value <0.05was considered statistically significant.

In the study period, 115 children with abdominal pain due to FAPDs wereenrolled and assigned to either neurostimulation (n=57) or sham device(n=47). Two patients were excluded due to a change in diagnosis afterstarting the study. One patient was found to have helicobacter infectionwith gastric ulcers and the second patient was found to haveeosinophilic esophagitis on endoscopy. Nine patients withdrew from thestudy after starting due to aesthetic reasons regarding the device.Median worst pain at baseline was very similar between placebo andtreatment group. Over time, a greater improvement in worst pain scoresfrom baseline was seen in the group with active treatment. This resultwas significant at all 3 weeks measured compared to placebo (p<0.001).At week 3, the placebo group had worse pain with a median of 7 comparedto treatment group 5 (p<0.001).

PFSD composite scores at baseline (22.8) were similar to those in thetreatment group (24.5). Composite scores in the treatment groupdecreased at week 1 (12.4), week 2 (12.0) and week 3 (8.4) (p<0.001). Nochange was seen from baseline in the placebo group in weeks 1 through 3(14.4, 14.7 and 15.2, respectively). At week 3, placebo group had worsetotal score with a median of 15.2 compared to the treatment group 8.4(p<0.005).

Using a ≥30% reduction in worst pain as a responder threshold, 60% ofpatients in the active treatment group improved compared to 22% in thecontrol group at week 3 compared to baseline (p<0.001). Similarly, byweek 3, 57% of patients in the treatment group had at least a 30%improvement in usual (average) pain scores from baseline compared to 29%in the placebo group (p=0.007).

Subjects rated their symptoms as better, worse or no change based on a15 point scale: −7 to −1=worse; 0=no change; +1 to +7=better). A scoreof +2 was considered to be significant improvement in global rating ofsymptoms. At the end of the 3 week treatment, the placebo group had amedian change in score of +1 (−5 to 6). The treatment group wassignificantly better at the end of 3 weeks with a median score of +3 (−3to 7) representing a large improvement in global rating of symptoms overplacebo (p<0.001).

From the entire cohort, 11 subjects reported side effects in bothgroups. Six patients reported ear discomfort, (4 of these patients hadactive device and 2 had sham device). Three patients had adhesivereactions, 1 patient developed dizziness and nausea after deviceplacement (active device). There was 1 patient in the placebo group whohad an episode of syncope prior to placement of device. This was laterdetermined to be related to needle phobia.

Treatment with Neuro-Stim device significantly improved worst pain andcomposite pain scores from baseline in all 3 weeks measured. There wasalso a improvement in the treatment group compared to placebo using theresponder definition of ≥30% improvement in weekly pain. Overall globalsymptoms improvement was significantly better in those with activetreatment compared to placebo.

We claim:
 1. A method of treating a disease comprising: alteringresponse characteristics of amygdala neurons and lumbar neurons, whereinthe altering step includes: stimulating a cranial nerve with anelectrical signal.